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Original Investigation | Epidemiology

Markers of Inflammation, Oxidative Stress, and Endothelial Dysfunction and the 20-Year Cumulative Incidence of Early Age-Related Macular Degeneration:  The Beaver Dam Eye Study

Ronald Klein, MD, MPH1,2; Chelsea E. Myers, MStat1; Karen J. Cruickshanks, PhD1,3; Ronald E. Gangnon, PhD2,3; Lorraine G. Danforth, BS1; Theru A. Sivakumaran, PhD4,5; Sudha K. Iyengar, PhD4; Michael Y. Tsai, PhD6; Barbara E. K. Klein, MD, MPH1
[+] Author Affiliations
1Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison
2Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison
3Department of Population Health Sciences, University of Wisconsin School of Medicine and Public Health, Madison
4Departments of Epidemiology and Biostatistics, and Genetics and Ophthalmology, Case Western Reserve University, Cleveland, Ohio
5Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
6Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis
JAMA Ophthalmol. 2014;132(4):446-455. doi:10.1001/jamaophthalmol.2013.7671.
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Importance  Modifying levels of factors associated with age-related macular degeneration (AMD) may decrease the risk for visual impairment in older persons.

Objective  To examine the relationships of markers of inflammation, oxidative stress, and endothelial dysfunction to the 20-year cumulative incidence of early AMD.

Design, Setting, and Participants  This longitudinal population-based cohort study involved a random sample of 975 persons in the Beaver Dam Eye Study without signs of AMD who participated in the baseline examination in 1988-1990 and up to 4 follow-up examinations in 1993-1995, 1998-2000, 2003-2005, and 2008-2010.

Exposures  Serum markers of inflammation (high-sensitivity C-reactive protein, tumor necrosis factor–α receptor 2, interleukin-6, and white blood cell count), oxidative stress (8-isoprostane and total carbonyl content), and endothelial dysfunction (soluble vascular cell adhesion molecule–1 and soluble intercellular adhesion molecule–1) were measured. Interactions with complement factor H (rs1061170), age-related maculopathy susceptibility 2 (rs10490924), complement component 3 (rs2230199), and complement component 2/complement factor B (rs4151667) were examined using multiplicative models. Age-related macular degeneration was assessed from fundus photographs.

Main Outcomes and Measures  Early AMD defined by the presence of any size drusen and the presence of pigmentary abnormalities or by the presence of large-sized drusen (≥125-μm diameter) in the absence of late AMD.

Results  The 20-year cumulative incidence of early AMD was 23.0%. Adjusting for age, sex, and other risk factors, high-sensitivity C-reactive protein (odds ratio comparing fourth with first quartile, 2.18; P = .005), tumor necrosis factor–α receptor 2 (odds ratio, 1.78; P = .04), and interleukin-6 (odds ratio, 1.78; P = .03) were associated with the incidence of early AMD. Increased incidence of early AMD was associated with soluble vascular cell adhesion molecule–1 (odds ratio per SD on the logarithmic scale, 1.21; P = .04).

Conclusions and Relevance  We found modest evidence of relationships of serum high-sensitivity C-reactive protein, tumor necrosis factor–α receptor 2, interleukin-6, and soluble vascular cell adhesion molecule–1 to the 20-year cumulative incidence of early AMD independent of age, smoking status, and other factors. It is not known whether these associations represent a cause and effect relationship or whether other unknown confounders accounted for the findings. Even if inflammatory processes are a cause of early AMD, it is not known whether interventions that reduce systemic inflammatory processes will reduce the incidence of early AMD.

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Figure.
Relationship of Markers of Inflammation, Endothelial Dysfunction, and Oxidative Stress to Early AMD Incidence

The graphs show the relationship of markers of inflammation, endothelial dysfunction, and oxidative stress to the 20-year incidence of early age-related macular degeneration in the Beaver Dam Eye Study (1988-1990 to 2008-2010) stratified by complement factor H rs1061170 genotype (A) and age-related maculopathy susceptibility 2 rs10490924 genotype (B). C indicates cytosine; G, guanine; hsCRP, high-sensitivity C-reactive protein; IL-6, interleukin-6; 8-ISO, 8-isoprostane; sICAM-1, soluble intercellular adhesion molecule–1; sVCAM-1, soluble vascular cell adhesion molecule–1; T, thymine; TCC, total carbonyl content; TNF-αR2, tumor necrosis factor–α receptor 2; WBC, white blood cell.

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